1. Technical Field of the Invention
The present invention relates to a novel process for the noncatalytic preparation of the 4-hydroxyquinolines and/or the tautomeric forms thereof.
This invention more especially relates to the preparation of 5,7-dichloro-4-hydroxyquinoline and/or tautomers thereof.
2. Description of the Prior Art
5,7-dichloro-4-hydroxyquinoline (DCHQ) is a known and valuable intermediate in the plant protection field.
The industrial scale preparation of such a product presents a variety of problems, and existing processes are in serious need of refining.
U.S. Pat. No. 5,731,440 and C. C. Price et al. (Organic Synthesis, 3, p. 272) describes the preparation of 4-hydroxyquinolines via a process entailing decarboxylation of 4-hydroxy-3-quinolinecarboxylic acids that have been obtained by alkaline or acid hydrolysis of the corresponding esters.
A process of that type has also been described in WO-A-98/33774, comprising hydrolyzing the ester function followed by acidification, separating the 4-hydroxy-3-quinolinecarboxylic acid obtained by filtration, then followed by decarboxylation carried out at a temperature from 190xc2x0 C. to 240xc2x0 C., preferably from 210xc2x0 C. to 230xc2x0 C.
One marked drawback of the above processes is the requirement for a base or an acid to conduct the hydrolysis, as this necessitates a neutralization step. Further, in the majority of instances the intermediate product, namely, 4-hydroxy-3-quinolinecarboxylic acid, has to be isolated, making the process more complex.
U.S. Pat. No. 4,380,632 proposes improving the above process by carrying out the decarboxylation step via heat treatment, in the presence of an acidic catalyst such as sulfuric acid, phosphoric acid, or p-toluenesulfonic acid. The hydrolysis and decarboxylation reactions take place at the same time. The presence of an acidic catalyst nonetheless entails supplemental neutralization and purification steps to eliminate the catalyst.
A novel process has now been discovered that improves hydroxyquinoline preparation, while at the same time avoiding the above disadvantages and drawbacks to date characterizing the state of this art.
Briefly, the present invention features the preparation of the hydroxyquinolines by heating a 4-hydroxyquinolinecarboxylic acid ester in the presence of water but in the absence of a catalyst.
More particularly according to the present invention, it has now unexpectedly and surprisingly been determined that the hydrolysis and decarboxylation of 4-hydroxyquinolinecarboxylic acid esters can be carried out in very high reaction yields, in the absence of a catalyst, which has the advantage of greatly simplifying the process.
The present invention thus relates to quinolinic compounds.
By the term xe2x80x9cquinolinic compoundxe2x80x9d is intended heterocyclic compound comprising a quinoline moiety. This term is also used for naphthpyridine type compounds that are also included in the scope of the process of the invention.
The heterocyclic ring member of the quinolinic compound is substituted by at least one hydroxyl group at the 4-position and an ester functional group at the position xcex1 to the hydroxyl group. Other substituents can also be present, in particular at the 5- and/or 7-position.
The starting material quinolinic compounds of the invention advantageously have the following structural formula (I): 
wherein the radicals R1, which may be identical or different, are each a linear or branched alkyl radical having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals; a linear or branched alkyl radical substituted by one or more halogen atoms and having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as halogenated methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals; a linear or branched alkenyl radical having 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, such as vinyl or allyl radicals; a cyclohexyl, phenyl or benzyl radical; a linear or branched alkoxy or thioether radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy or butoxy radical; an acyl radical having 2 to 6 carbon atoms; a nitro group; an amino group, optionally substituted by alkyl radicals having 1 to 6 carbon atoms; a halogen atom, preferably a chlorine or bromine atom; a trifluoromethyl radical; or an alkenylene radical having 3 or 4 carbon atoms and forming a ring member with the adjacent carbon atoms of the benzene moiety; R2 is an alkyl radical having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals; a cycloalkyl radical having 5 or 6 carbon atoms, preferably a cyclohexyl radical; an aryl radical having 6 to 12 carbon atoms, preferably a phenyl radical; or an arylalkyl radical having 7 to 12 carbon atoms, preferably a benzyl radical; and n is a number ranging from 1 to 4, preferably 1 or 2.
Particularly suitable substituents at the 5- and/or 7-position are halogen atoms, such as fluorine, chlorine, bromine, iodine or a xe2x80x94CF3 radical.
Preferred substituents R1 are the chlorine atom, methyl radical and methoxy radical.
The chemical nature of R2 is not critical provided that the carboxylate group is eliminated. For reasons of economy, it is usually a linear or branched alkyl radical having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, but it is possible to employ other radicals, for example cyclohexyl, phenyl or benzyl radicals, or any other group.
Preferred compounds of formula (I) according to the process of the present invention are alkyl esters having 1 to 4 carbon atoms of 4-hydroxyquinolinecarboxylic acids.
Particularly representative are the alkyl esters of 4-hydroxy-7-chloroquinolinecarboxylic acid, 4-hydroxy-5-chloroquinolinecarboxylic acid and 4-hydroxy-5,7-dichloroquinolinecarboxylic acid.
Preferably, methyl or ethyl 4-hydroxy-5,7-dichloroquinoline-3-carboxylate are the starting materials of choice in the process of the invention.
The starting quinolinic compounds of formula (I) are known compounds that can, in particular, be prepared by reacting substituted anilines with alkyl alkoxymethylenemalonates (cf. C. C. Price et al., Organic Synthesis, 3, p. 272).
It should be appreciated that this invention is applicable to quinolinic compounds of formula (I) and also to the tautomeric forms thereof that can be represented by the structural formula (II): 
in which formula (II), R1, R2 and n have the definitions given above for formula (I).
According to the process of the invention, the hydrolysis step is carried out using water in either its liquid and/or vapor form.
The amount of water employed is preferably at least equal to the stoichiometric amount, more preferably in an excess amount which can be very large, for example 20 times the stoichiometric amount. Advantageously, the water is present in an excess of 5 to 15 times the stoichiometric amount.
Preferably, the water is added slowly during the reaction to limit entrainment of the organic liquid.
The decarboxylation is carried out either by heating the reaction mixture in the absence of any organic solvent to its melting point, or to a temperature slightly lower than its melting point in the event of decomposition of the starting material, or by heating in the presence of a heat exchange type organic liquid having a high boiling point.
The decarboxylation temperature is preferably 200xc2x0 C. or more, more preferably in the range 200xc2x0 C. to 250xc2x0 C., and even more preferably in the range 230xc2x0 C. to 240xc2x0 C. A temperature above 250xc2x0 C. can be employed depending on the nature of the organic liquid. It is about 270xc2x0 C. when using a paraffin oil.
One organic liquid that is preferred for this type of reaction is a eutectic mixture of biphenyl oxide and biphenyl marketed under the trademarks THERMINOL VP1, DOWTHERM or GILOTHERM DO. When the organic liquid is indeed used, the decarboxylation temperature is advantageously selected such as to be in the preferred temperature zone.
Triphenylmethane, sulfolane, benzylbenzene, 1,4-dibenzylbenzene, a silicone oil, or petroleum cuts, having a high boiling point greater than the selected reaction temperature, can also be used.
From a practical standpoint, in general the quinolinic compound is introduced into the organic liquid indicated above in an amount, for example, of 10% to 50% by weight, preferably 10% to 30% by weight of the total weight of the reaction mixture, then heated slowly to the selected decarboxylation temperature (0.5xc2x0 C. to 1xc2x0 C. per minute). It is not necessary for all of the entire starting material to be dissolved in the reaction medium.
Water is slowly added at the selected reaction temperature.
Upon completion of the operation, a precipitate is recovered that essentially comprises the desired quinolinic compound (B) in equilibrium with its tautomeric form (A), having the following formulae: 
wherein R1 and n are as defined above.
The precipitate is separated employing conventional solid/liquid separation techniques, preferably by filtering.
Washing the precipitate to eliminate trace amounts of organic liquid may be desirable. To this end, water or a solvent having a low boiling point, can be used, for example less than 150xc2x0 C., preferably in the range 60xc2x0 C. to 120xc2x0 C. Particularly exemplary of eminently suitable solvents are o-dichlorobenzene, methylcyclohexane, benzene, toluene, chlorobenzene, methanol and ethanol.
The decarboxylated compound is obtained in a very high yield without the problem of neutralization and eliminating the catalyst.
The present invention is particularly well suited for the preparation of a 4-hydroxy-7-halogenoquinoline, preferably 4-hydroxy-7-chloroquinoline and isomer thereof, and a 4-hydroxy-5-halogenoquinoline, preferably 4-hydroxy-5-chloroquinoline. It is very well suited for preparing 5,7-dichloro-4-hydroxyquinoline.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.